Our group used functional neuroimaging to determine local neuronal activity in patients with schizophrenia and other neuropsychiatric disorders during performance of working memory and abstract reasoning tasks as well as during performance of matched sensorimotor control tests and other contrast tasks. By using a 2-back version of an N-back continuous working memory task, we have re-confirmed previous findings derived from the Wisconsin Card Sorting Test (WCST) of dysfunction of prefrontal cortex. As in previous studies, the aberrant activation pattern appears to occur even in patients who perform relatively well on the task. We also examined changes in cognitive activation across several time points during a medication-free period in individual patients. This determined the relationship between the physiological changes and concomitant changes in symptoms and cognitive performance. Further analyses of the time course of these changes are ongoing. We have also explored the functional connectivity among various nodes of the working memory system using eigenimage analysis. This has shown that more than half the intergroup variance (across controls and patients) was explained by a single pattern showing inferotemporal-hippocampal-cereballar loading for patients versus dorsolateral-prefrontal-cingulate activity for controls. Expression of this pattern perfectly separated all patient scans from the control group, a finding prospectively validated in two new data sets, suggesting that it may be a trait marker. Another pattern accounting for 20% of the variance demonstrated that expression of the working-memory-related network was significantly more variable in patients than that in control subjects, suggesting a systems-level explanation for the findings of hypofunction. We have further demonstrated that an important component of this pattern lies in specific abnormality in the functional relationship between the dorsolateral prefrontal cortex (DLPFC) and the hippocampus. We have also shown that even when patients with schizophrenia are compared with young normal subjects with equally poor performance, they still have diminished prefrontal cortical response while performing tasks with a strong working memory component. Moreover, patients with schizophrenia still show reduced activation of the prefrontal cortex when compared with healthy, elderly subjects matched with them on a one-to-one basis for WCST performance. In this schizophrenic group, reduced activation in the DLPFC correlated with more perseveration during the WCST. In contrast, in the elderly subjects DLPFC activation is preserved and does not correlate with performance, suggesting that other mechanisms may account for their cognitive impairment on this task. [unreadable] [unreadable] We have initiated a number of cross-modal neuroimaging studies in schizophrenia. We previously found that prefrontal N-acetyl-aspartate magnetic resonance spectroscopy signal predicts impaired WCST rCBF activation not only in the prefrontal cortices of our patients, but also in other nodes in the working memory system. This relationship was found in patients, but not in control subjects, and not with NAA (N-acetylaspartate) in other brain regions. Additionally, to test the hypothesis that exaggerated striatal dopaminergic neurotransmission in schizophrenia is a consequence of DLPFC dysfunction, we used positron emission tomography (PET) to determine whether and how abnormal striatal presynaptic dopaminergic neurotransmission and disturbed prefrontal cortical function interact in schizophrenia. In a single PET session we determined both prefrontal activity (measured with regional cerebral blood flow) during the WCST and presynaptic dopaminergic function (measured with the PET tracer 6-18F-DOPA FDOPA, uptake of which depends on the rate of dopamine biosynthesis), in patients withdrawn from medication for four weeks and matched controls. Striatal FDOPA uptake in patients was significantly higher than in normal controls, while WCST-related activity in prefrontal cortex was decreased. Most importantly, in patients there was a highly significant negative correlation between task-related prefrontal and striatal dopamine uptake which was absent in controls. This study provided a mechanistic explanation for the coexistence of two key pathophysiological hallmarks of schizophrenia.